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MDS Management: ASCERTAIN Equivalence Study


Experts reflect on results from the phase 3 ASCERTAIN equivalence study of oral decitabine/cedazuridine in myelodysplastic syndrome.


Bart Scott, MD, MS: There is an exciting study that’s been completed. It’s called the ASCERTAIN trial, and it’s a phase 3, randomized study evaluating oral decitabine. It’s a combination of cedazuridine with decitabine, and it’s an oral formulation of hypomethylating therapy.

The trial gave patients either oral decitabine or cedazuridine/decitabine combination up front, then followed by IV [intravenous] decitabine, or IV decitabine followed by the oral administration of the cedazuridine/decitabine compound. One of the end points of this study was to follow the half-life or the pharmacokinetics of the drug. That tells us how well the drug is being absorbed. If the drug is present within the blood stream at equivalent levels, then the route of administration should not matter.

That’s a statement of fact, but it is important to say that it’s not necessarily a fact. There are some who might argue with that statement because showing that the blood levels are equivalent from people doesn’t necessarily answer all the questions that you might have in regard to how the drug works. For example, does it result in similar survival rates? Does it result in similar transfusion independence rates? These are questions that people might have about the ASCERTAIN trial, but right now we can say that it met its primary end point in showing pharmacokinetic equivalence between the oral route of administration and the IV route of administration.

The reason that’s exciting is because patients face challenges in coming into clinic to receive a medication, and if they can take a pill formulation, then that would be less challenging for them. It would also likely improve compliance. And there are some who might argue that the oral route of administration could result in longer duration of exposure, and that it is the longer duration of exposure that will result in the best clinical outcomes rather than the peaks and valleys that patients get from an IV administration.

This last component needs to be borne out through further follow-up and more data. We have to be cautious when we look at how we interpret the information we have, and we can’t necessarily say that the oral route of administration is superior yet. That is what people might hope for: if we can deliver a drug in a more continuous way, we can potentially improve response rates, but we don’t know that for sure yet.

Amer Zeidan, MBBS, MHS: In terms of clinical efficacy, the data that were presented at the American Society of Hematology [Annual] Meeting [and Exposition] in December of 2019. That was the first analysis from the trial, and subsequent analyses are going to continue. It sounds like the activity with the oral decitabine is somewhat similar to the IV decitabine in terms of complete response rate, transfusion independence, as well as overall survival. To get the definitive sense of that, you need the randomized trial of IV versus oral, but that could take many more years. This approach of looking at pharmacokinetic equivalence was a smart approach to make that drug potentially available faster for patients to give them that alternative.

For hypomethylating agents, the development of oral versions is one of the more important developments in the field of myelodysplastic syndromes. The development of C-DEC , an oral version of decitabine with cedazuridine, which is an oral agent that inhibits the enzyme that metabolizes decitabine in the intestine or in the liver. Because of that enzyme, we are not able to get decitabine orally. However, with the use of this agent, we are now able to block this enzyme, and that allows the absorption of decitabine, and therefore it can be given orally. That's important because it allows administration of the drug without needing to have an intravenous access and potentially without having to come to the clinic frequently.

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